Introduction
Rosai-Dorfman disease (RDD), originally described as sinus histiocytosis with massive lymphadenopathy by Rosai and Dorfman in 1969, is a rare, non-Langerhans cell histiocytosis of unknown origin [1]. It primarily affects children and young adults but can present at any age. While most cases involve bilateral cervical lymph nodes, extranodal manifestations are also observed [2], which may necessitate careful monitoring, steroid therapy, or chemotherapy [3].
Rosai-Dorfman disease often mimics malignancies, infections, or autoimmune disorders, posing a significant diagnostic challenge. Typical symptoms include painless cervical lymphadenopathy, fever, night sweats, and weight loss. Extranodal sites are affected in approximately 43% of cases, with common locations including the nasal cavity (11%), orbital tissue (11%), skin (10%), bones (5–10%), central nervous system (5%), and salivary glands [2, 4]. Laboratory findings may reveal leucocytosis, elevated erythrocyte sedimentation rate (ESR), hypergammaglobuliaemia, and autoimmune haemolytic anaemia [4, 5].
Histopathological examination is essential for diagnosis, often showing emperipolesis (engulfment of inflammatory cells by histiocytes), a hallmark of RDD, though not pathognomonic. Immunohistochemical analysis is critical for confirming the diagnosis and excluding other causes, including infections [2]. Due to its unknown pathogenesis, nonspecific symptoms, and variable presentations, RDD can closely resemble more severe diseases with entirely different management strategies. Prompt and accurate diagnosis is thus vital for ensuring appropriate treatment and a better outcome.
We report the case of a patient with RDD mimicking a malignant proliferative process and IgG4-related disease. The patient underwent a complex 2-year diagnostic journey across several hospitals. This case highlights the importance of multidisciplinary collaboration, holistic diagnostic approaches, and further research to deepen the understanding of this rare disease.
Case report
A 73-year-old male was admitted to the Department of Rheumatology with a 2-year history of general malaise, significant weight loss (20 kg in 2 years), subfebrile states, fevers, and cervical lymphadenopathy. Despite a detailed diagnostic process, no diagnosis had been reached. Laboratory tests revealed elevated inflammatory markers (C-reactive protein [CRP] 158 mg/l and ESR 121 mm/h). Endoscopic examinations of the gastrointestinal tract did not reveal any evidence of malignancy, while positron emission tomography-computed tomography showed numerous metabolically active foci in lymph nodes of the head and neck (SUVmax up to 5.2) as well as the chest (SUVmax up to 7.1), paranasal sinuses (SUVmax up to 8.4), and bones (SUVmax up to 10.1) – suggestive of malignancy or a proliferative process. A bone marrow biopsy showed non-specific granulocytic abnormalities, and multiple myeloma was excluded through blood and urine tests. Biopsies of lymph nodes, paranasal sinus mucosa, and bone showed reactive changes and chronic inflammation. Despite broad-spectrum antibiotics for suspected osteomyelitis, symptoms persisted. Infectious causes such as Lyme disease, syphilis, and tuberculosis were excluded.
Ten months later, the patient developed parotid and submandibular gland enlargement. Elevated IgG4 levels (3583 mg/dl) were found at the Department of Internal Diseases, leading to a suspicion of IgG4-related disease (IgG4-RD). Steroid therapy improved symptoms and stabilised weight loss, prompting referral to the Rheumatology Department for confirmation. Upon admission, examination revealed enlarged lymph nodes (up to 25 mm on the left and 20 mm on the right in ultrasound examination and parotid and submandibular glands, and an oral lesion resembling leukoplakia. Laboratory tests showed elevated inflammatory markers (CRP 70 mg/l, ESR 69 mm/h, ferritin 414 ng/ml), anaemia of chronic disease (Hgb 12.2 g/dl, MCV 88 fl, iron 2.5 µmol/l, total iron binding capacity 40.0 µmol/l), hypergammaglobulinaemia (19.9 g/l) with hypoalbuminaemia (30.7 g/l), elevated IgE (255 IU/ml), and IgG (21687 mg/l), including IgG4 (3583 mg/l). The IgG4/IgG ratio, however, was low (16.52%). Antinuclear antibody was positive in a titre of 1 : 320 with granular pattern and 1 : 160 with cytoplasmic pattern, but without disease-specific antibodies (Table 1).
Table 1
The patient’s laboratory test results upon admission to the Rheumatology Department
[i] A/G ratio – albumin-globulin ratio, ANA – antinuclear antibody, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, HCT – haematocrit, HGB – haemoglobin, IgE – immunoglobulin E, IgG – immunoglobulin G, MCH – mean corpuscular haemoglobin, MCHC – mean corpuscular haemoglobin concentration, MCV – mean corpuscular volume, RDW – red cell distribution width, TIBC – total iron binding capacity
Ultrasound excluded significant salivary gland enlargement but identified lymph nodes within the glands. Gaucher’s disease was excluded via a dried blood spot test. A biopsy of the oral lesion showed reactive changes. Computed tomography revealed prostate calcifications suggestive of a malignancy, generalised lymphadenopathy, osteosclerotic bone lesions, minor pulmonary embolism, and slightly enlarged parotid glands. Prostate cancer, histiocytosis, and IgG4-RD were considered. Prostate-specific antigen (PSA) levels were normal (total PSA level was 1.28 ng/ml), and pelvic magnetic resonance imaging revealed oncologically suspicious foci, which, upon targeted biopsy, excluded malignancy. Skeletal scintigraphy revealed metabolic activity in multiple bones.
A nuchal lymph node biopsy showed effaced architecture with sinusoidal dilatation, numerous large histiocytes (Figs. 1 A, B) without atypia, and a low Ki-67 index (< 5%). Immunophenotyping of histiocytes showed CD68 expression, positivity for S100, and negativity for CD1a (Fig. 1 C). Emperipolesis was observed (Fig. 1 D). Further studies confirmed this with OCT2 and cyclin D1 expression in histiocytes. The histiocytic infiltrates were accompanied by diffuse plasma cell infiltrates without evidence of κ/λ light chain restriction and without features of IgG4-RD (IgG4/IgG ratio < 0.4, although IgG4+ cells were relatively numerous). Histopathological findings and clinical data, along with exclusion of other conditions, led to a diagnosis of RDD.
Fig. 1
Low-power histopathological image of nodal Rosai-Dorfman disease, displaying alternating light and dark areas. The lighter regions consist of numerous histiocytes with abundant pale pink cytoplasm, while the darker areas are composed of plasma cells and lymphocytes (HE, 25×) (A), high-power view highlighting characteristic histiocytes with abundant pale pink cytoplasm, vesicular nuclei, and prominent nucleoli, with visible emperipolesis (HE, 200×) (B), immunohistochemical staining reveals CD1a negativity in histiocytes (100×) (C), immu nohistochemistry demonstrates S-100 positivity in histiocytes and highlights emperipolesis, visible as unstained inflammatory cells within the S100-positive cytoplasm of histiocytes (100×) (D)
The patient was treated with intravenous methylprednisolone (3´), followed by prednisone (40 mg/day) in the Department of Rheumatology. Subsequently, the patient was referred to the Department of Haematology, where prednisone administration at a dose of 40 mg/day was continued, resulting in partial improvement. After one month, methotrexate (MTX) was added (25 mg/week) while gradually reducing the prednisone dose. General symptoms resolved, but mild lymphadenopathy persisted. After a few months, the prednisone dose was reduced to 10 mg/day (attempts to reduce the dose to 7.5 mg/day resulted in a relapse of fevers), while the MTX dose was increased to 30 mg/week. The last follow-up was in late December 2024, and a significant improvement in clinical condition was observed.
Discussion
The presented case highlights the broad clinical manifestations of RDD and the significant diagnostic challenges it poses. As demonstrated here, RDD can mimic various conditions, including malignancies, IgG4-RD, and other histiocytoses, which differ greatly in terms of treatment. Correct and prompt diagnosis is crucial for the patient’s outcome, and this case further underscores the need for intensive research to better understand RDD, with the goal of improving diagnostics and treatment.
Lymph node involvement, observed in 87% of cases, is the most common clinical feature of RDD. Typically presenting as bilateral, painless cervical lymphadenopathy, it can also involve mediastinal, inguinal, or retroperitoneal lymph nodes. In our patient, significant lymphadenopathy was observed in multiple regions, including cervical, mediastinal, axillary, and submandibular lymph nodes. General symptoms such as fatigue, fever, and weight loss – frequently reported in RDD – were prominent features in this case. Laboratory findings, consistent with the literature, showed increased ESR, polyclonal hypergammaglobulinaemia, elevated ferritin, and leucocytosis [4, 5].
Extranodal involvement, seen in over 40% of RDD cases, is diverse, with common sites including retro-orbital tissue (11%), nasal cavity (11%), skin (10%), bones (10%), central nervous system (5%), and salivary glands. In our patient, extranodal lesions were identified in bones and salivary glands, aligning with reported sites of involvement [2, 4]. Bone lesions, such as those observed in this case, can affect various bones, including the tibia, femur, clavicle, and skull. Radiographically, the lytic, multiloculated, and well-defined lesions with sclerotic borders in our patient matched typical imaging findings in RDD [6]. While lymph node involvement often accompanies bone lesions, the extent of lymphadenopathy in this case further complicated the diagnostic process, highlighting the complexity of RDD presentations [7].
The differential diagnosis in this case was particularly challenging. Elevated IgG4 levels, combined with systemic symptoms and lymphadenopathy, initially raised suspicion for IgG4-RD. The improvement with glucocorticosteroids was consistent with this diagnosis; however, bone lesions and chronic fever are exclusion criteria for IgG4-RD [8]. Histopathologically, differentiation between RDD and IgG4-RD requires detailed analysis because IgG4+ plasma cells are often present in RDD, but the IgG4/IgG ratio remains < 40%, and storiform fibrosis, a hallmark of IgG4-RD, is absent [9]. A detailed differential diagnosis between these 2 conditions is highly complex and extends beyond the scope of this paper [2, 10]. Erdheim-Chester disease (ECD) was another consideration due to the patient’s age, male gender, and osteosclerotic bone lesions. Metabolically active skeletal lesions and raised CRP levels further suggested ECD. However, lymphadenopathy and chronic fever are not typical for ECD [11]. Histopathological evaluation showed key distinguishing features, such as the absence of Touton giant cells and positive S-100 expression by histiocytes, ruling out ECD [12]. Langerhans cell histiocytosis was considered due to osteolytic bone lesions, particularly in the skull and vertebral bodies. However, the lack of CD1a and CD207 expression, which are characteristic markers of Langerhans cell histiocytosis, definitively excluded this condition [13]. Additional features, such as dense plasma cell infiltrates in RDD and the absence of an eosinophilic component, further differentiated the two [2]. A summary of the immunophenotype of histiocytes in these diseases is provided in Table 2 [2, 12, 13]. Generalised symptoms, such as weakness, fever, and weight loss, combined with metabolically active skeletal and lymph node foci, initially raised suspicion of disseminated prostate carcinoma. However, the PSA level was not significantly elevated, and the prostate biopsy was negative for malignancy.
Table 2
Summary of the diagnostic markers of histiocytes in histiocytoses included in differential diagnosis
| Diagnostic marker | RDD | ECD | LCH |
|---|---|---|---|
| S100 (IHC) | + | – | + |
| CD1a (IHC) | – | – | + |
| CD68 (IHC) | + (variable) | + | + |
| CD163 (IHC) | + (variable) | + | + |
| CD207 (langerin, IHC) | – | – | + |
| OCT2 (IHC) | + | – | – |
| Cyclin D1 (IHC) | + | – | – |
| BRAF p.V600E (IHC, genetic) | – | + | + |
This case adds to the growing body of evidence supporting the successful use of MTX in the treatment of RDD. While glucocorticosteroids initially alleviated symptoms, MTX represents a promising option for systemic cases. The patient’s favourable response to MTX highlights its therapeutic potential and aligns with other reports of its efficacy [14].
Conclusions
This case highlights the diagnostic complexity of RDD, which presents with diverse clinical manifestations and can closely mimic malignancies, IgG4-related disease, and other histiocytoses. Achieving an accurate diagnosis requires a multidisciplinary approach, combining clinical assessment, advanced imaging, and detailed histopathological and immunophenotypic analyses. Moreover, this report adds to the growing evidence supporting the successful use of antimetabolites as an effective treatment option for systemic RDD.
